Mechanism Of Action And Biomarker Strategy For Hfb200301, An Anti-Tnfr2 Agonist Antibody For The Treatment Of Cancer.

Abstract Despite the success of immune check point inhibition, identification of other pathways capable of modulating the immune response against the tumor remains challenging. T-cell co-stimulation has been investigated with limited clinical success so far due in part to the fine tuning required for agonist antibodies against those co-stimulatory receptors and to the lack of biomarkers to facilitate the selection of patients likely to benefit from T-cell co-stimulation. TNFR2 belongs to the TNFR family of costimulatory molecules, and its expression on tumor infiltrating lymphocytes across a wide range of tumors make it an attractive target for T-cell co-stimulation. Recently, we identified HFB200301, an anti-TNFR2 antibody with Fc-independent agonist activity that does not block TNFR2 interaction with TNFα. HFB200301 activates CD4+, CD8+ T cells, and NK cells in vitro. In vivo, HFB200301 demonstrated potent single agent anti-tumor activity in syngeneic tumor models and can further increase the antitumor activity in combination with PD-1 blockade. To understand the immunological basis for the anti-tumor efficacy of HFB200301, we investigated the pharmacodynamic effects of HFB200301 in syngeneic mouse tumor models, including immuno-phenotyping and receptor occupancy of tumor infiltrating cells. In hTNFR2 knock-in mice bearing MC38 tumors, HFB200301 induces expansion of CD4+ and CD8+ T cells, and NK cells in the tumor micro-environment without affecting regulatory T cell numbers. We also demonstrate that the anti-tumor efficacy of HFB200301 is correlated with receptor occupancy and circulating soluble TNFR2 in a dose-dependent manner in this model. To discover predictive biomarkers of response to HFB200301, we used primary tumor samples and our proprietary Drug Intelligent Science (DIS™) single-cell platform to establish an immune-related signature. Single-cell RNA sequencing and clonotype barcoding of ex-vivo tumor cultures treated with HFB200301 were used to identify unique T cell profiles with a T cell centric gene panel. These unique T cell profiles may help identifying patients more likely to respond to HFB200301 treatment. In summary, HFB200301 exhibits a unique mechanism of action mainly relying on its agonistic activity on several effector cell types in tumor micro-environment that we expect will benefit a patient population selected with a unique biomarker signature. HFB200301 is currently in preclinical development and a biomarker-driven Phase 1 clinical study is projected for 2021. Citation Format: Shuo Wei, Ross Fulton, Yun-Yueh Lu, Qian Zhang, He Zhou, Andreas Raue, Mingjie Chen, Wenhua Xu, Xing Cai, Juliana Crivello, Zachary Duda, Zhiyuan Wang, Rebecca Silver, Alexandra Staskus, Charina Ortega, Sami Ellouze, Carine George, Sophie Foulon, Dean Lee, Monika Manne, Nicola Beltraminelli, Jinping Gan, Francisco Adrian, Liang Schweizer, Jennifer Watkins-Yoon. Mechanism of action and biomarker strategy for HFB200301, an anti-TNFR2 agonist antibody for the treatment of cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1883.